Detecting melanoma early leads to a nearly 100% cure rate, but diagnosing it at an advanced stage results in less than 20% survival. The power of early diagnosis has made it the major approach to preventing death from melanoma. Yet there is little evidence that large public skin cancer screenings prevent melanoma deaths. Focusing on people at greatest risk would be possible with an early predictor of risk that helps the primary care physician identify patients who should be followed by a dermatologist. This preventive test needs to measure both aspects of melanoma risk: genetic risk and sun-exposure risk. Project 1 focuses on sun-exposure risk because most people with Fitzpatrick Type I skin do not get melanoma. Yet UV exposure is usually ascertained by patient recollections rather than by objective biological indicators of past sun exposure. To overcome this critical barrier to assessing personal UV exposure and thus melanoma risk, we propose to couple two new technologies with Next-Gen sequencing to create genomic surrogate biomarkers of long-term sun exposure. One dosimeter takes advantage of the accumulation of DNA photoproducts in special regions of the genome; the other incorporates our knowledge about clonal expansion of cells in skin. We then evaluate these genomic dosimeter readings in skin for association with melanoma. The Specific Aims are: Aim 1: Map human genomic regions that are UV damage hotspots or DNA repair slowspots. Aim 2: Quantitate rare UV-mutated genes in skin in vivo. Aim 3: Use genomic regions sensitive to UV photoproducts and mutations as dosimeters to correlate cumulative sunlight exposure in normal skin to risk for melanoma. These studies establish ways to objectively ascertain exposure to cancer risk using modern measurement technologies.